This R21 application is in response to a Request for Proposals for studies that will develop an "understanding of the role of innate immunity in the etiopathogenesis of autoimmune rheumatic diseases," with particular relevance to an understanding of "the earlier events of the etiopathogenesis of disease." To this end, we have united two new approaches. The molecular focus of our studies is SHPS-1, a regulatory receptor that is expressed primarily on cells of macrophage lineage. SHPS-1 regulates the activation of innate immunity and the consequent activation of adaptive immunity, as well as leukocyte migration and the formation of osteoclasts from macrophages. Thus, SHPS-1 has the potential to regulate the interactions between the innate immune system (macrophages) and adaptive immunity (lymphocytes) at many points in the development of autoimmunity, but its role in autoimmunity has not previously been studied. We propose to do so through the study of a new mouse model for rheumatoid arthritis, SKG mice, in which the development of arthritis is heavily dependent on activation of the innate immune system. Our goal is to develop and characterize 3 models in which the role of SHPS-1 in the RA-like disease of SKG mice can be studied. These are: 1. SKG mice treated in vivo with a blocking monoclonal antibody to SHPS-1. 2. SKG mice in which SHPS-1 lacks the cytoplasmic domain. 3. SKG mice in which SHPS-1 is not expressed at all. If these models support a role of SHPS-1 in the regulation of arthritis, they will provide excellent models to dissect the cellular interactions that elicit the RA-like disease in SKG mice. Because SHPS-1 has a close homologue in humans (SIRPal), the results may have direct application to patients with RA.